Science Editor

Scientists have identified a steroid hormone in the brain – ADIOL, a precursor of both androgen and estrogen – that prevents neuroinflammation by signaling through the estrogen receptor beta on several types of brain support cells.

Ironically, estrogen itself does not have the same anti-inflammatory effects as ADIOL. In fact, it appears to antagonize the effects of ADIOL.

The work, which was published in the May 13, 2011, issue of Cell, came out of studies to understand the epidemiology of multiple sclerosis.

That disease "affects primarily young women," Kaoru Saijo told BioWorld Today. "And we wondered, 'why is that?'" Saijo is first author of the paper, which appeared in the May 13, 2011, issue of Cell, and an associate project scientist in the lab of senior author Christopher Glass at the University of California, San Diego.

The fact that women of childbearing age are the most frequent victims of multiple sclerosis, as well as some previous studies on the topic, made estrogen signaling an obvious possibility.

The authors began their studies by using a series of small molecules to study the effects of blocking estrogen receptor beta signaling in the brain.

"The estrogen receptor beta was not much focused on in the past," Saijo said, being thought of as alpha's less important sibling. Estrogen receptor alpha, which is expressed mainly in the reproductive organs, is indeed the main mediator of estrogen's classical effects as a female sex hormone.

But estrogen receptor beta is more widely expressed in the brain. And in their studies, her team found that certain estrogen beta ligands were able to suppress inflammatory signals in microglia – brain cells that play important roles in immunity and inflammation instead. Estrogen beta receptor signaling also reduced the proinflammatory signaling of astrocytes, another brain immune cell that amplifies the microglial responses.

The compounds appeared to work by recruiting inhibitory co-factors and so indirectly preventing the expression of genes that normally induce microglia to make and release proinflammatory signals. Those signals, in turn, activate T cells.

The system is important for fighting infections, but suffers from the same Achille's heel as other inflammation-dependent processes. If the inflammatory signals cannot be reined in once the infection is over, the inflammation turns on itself. Such processes play an important role in multiple sclerosis and other brain diseases where inflammation plays a role.

The authors found that targeting estrogen receptor beta signaling could affect well-established chronic inflammation and autoimmunity. Mice with experimental autoimmune encephalitis, an animal version of multiple sclerosis, had improved symptoms when they were treated with estrogen-beta modulators three weeks into the disease.

Saijo and her team knew that if small molecules could affect estrogen receptor beta signaling, "there must be a natural product on the brain" capable of the same feat. So they next searched for the endogenous signaling molecule that affects estrogen beta receptors.

They tested a number of steroid hormones for their ability to suppress proinflammatory signaling in cell culture, and found that ADIOL, a precursor of both androgen and estrogen, had the strongest effects. Estrogen, on the other hand, was not able to exert anti-inflammatory effects in the cells the authors tested.

In fact, the research suggested that women may be more vulnerable to autoimmune disease because estrogen competes with ADIOL for estrogen receptor binding, partially nixing its protective effects.

Saijo said that her team hopes the findings will "help us understand inflammation states" in autoimmune patients.

For now, the team is testing whether the effects of estrogen receptor signaling are specific to multiple sclerosis – or, as the authors expect, apply to neuroinflammation more generally. The authors are testing animal models of Alzheimer's disease, Parkinson's disease and HIV-related dementia. All three are neurological conditions that are driven at least in part by inflammation.

The authors also hope ADIOL might be used as a biomarker. They plan to test whether blood levels of ADIOL correlate with disease severity, first in HIV-related dementia and then in other disorders as well.

Ultimately, Saijo said, the approach might also lead to new therapeutic avenues for neuroinflammation.

That's really far away," she said. "But it is our dream."